CYCLIC GUANOSINE-MONOPHOSPHATE AS A MEDIATOR OF VASODILATION
CYCLIC GUANOSINE-MONOPHOSPHATE AS A MEDIATOR OF VASODILATION
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DOI：
10.1172/jci112536
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发表时间：
1986-07-01
影响因子：
15.9
通讯作者：
MURAD, F
中科院分区：
文献类型：
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作者：
MURAD, F
尽管环鸟苷一磷酸（GMP β）在二十多年前首次在生物样品中被描述，但其在某些生理过程中的作用仅在过去几年中才变得明显（参见参考文献1-4）。这种相对缓慢的发展可能是由于组织中核苷酸浓度低，早期研究中复杂和不敏感的方法，以及许多研究人员对其可能功能的偏见。后者无疑是受到环GMP系统与环AMP系统的许多相似性以及环AMP在此期间受到的关注的影响。虽然这两个环核苷酸系统之间确实存在类似性和相似性，但由于存在负责其合成的几种同工酶，环GMP系统呈现出更复杂的情况。已知鸟苷三磷酸（GTP）转化为环GMP由鸟苷酸环化酶的至少两种同工酶形式催化。胞质同工酶和膜相关同工酶的动力学、物理化学和抗原特性完全不同（见参考文献2、4）。可溶性和颗粒酶的相对丰度在不同组织和物种中是可变的。虽然肠粘膜和视网膜主要具有颗粒同工酶，血小板含有可溶性同工酶，但大多数组织如血管平滑肌都具有这两种同工酶。此外，这些同工酶的调节也有很大的不同。这种可溶性酶的独特之处在于它可以被活性自由基激活，如一氧化氮（5），可能还有羟基自由基（6）和一些卟啉（7，8）。另一方面，颗粒状同工酶可以用诸如大肠杆菌热稳定肠毒素（9- 11）、心房肽（12，13）和氯化血红素（14）的试剂活化。阳离子、硫醇、其他氧化还原剂和去污剂对这两种同工酶的活性也有复杂的影响（2）。对这些同工酶的动力学特征的研究导致了目前对环GMP在平滑肌松弛中的作用的理解。在粗酶制剂中加入叠氮化物以抑制GT酶活性，发现叠氮化物可激活酶（15）。虽然一些激素、autocoids和其他药物能够增加完整组织中的cGMP积累，但这些药物对受损组织中的鸟苷酸环化酶活性没有影响。
Although cyclic guanosine monophosphate (GMP)'was first described in biological samplesmore than two decades ago, its role in some physiological processes has only become apparent in the past few years (see references 1-4). This relatively slow development is probably attributable to the low concentrations ofthe nucleotide in tissues, the complex and insensitive methods available during the early studies, and the biases many investigators had regarding its possible functions. The latterwas un-doubtedly influenced by the many similarities ofthe cyclic GMP system with that of cyclic AMP and the attention cyclic AMP has received during this period. While analogies and similarities between these two cyclic nucleotide systems do exist, the cyclic GMP system presents more complexities due to the existence of several isoenzymes responsible for its synthesis. It is known that the conversion of guanosine triphosphate (GTP) to cyclic GMP is catalyzed by at least two isoenzyme forms of guanylate cyclase. The kinetic, physicochemical, and antigenic properties of the cytosolic and membrane-associated isoenzymes are quite different (see references 2, 4). The relative abundance of the soluble and particulate enzyme is variable in different tissues and species. While intestinal mucosa andretina possess predominately the particulate isoenzyme and platelets contain the soluble isoenzyme, most tissues such as vascular smooth muscle have both isoenzymes. Furthermore, the regu-lation ofeach ofthese isoenzymes is quite different. The soluble enzyme appears uniquein that it can be activated by reactive free radicals suchas nitric oxide (5), and probably hydroxyl free radical (6) and some porphyrins (7, 8). On the other hand, the particulate isoenzyme can be activated with agents such as Escherichia coli heat-stable enterotoxin (9-1 1), atriopeptins (12, 13), and hemin (14). Cations, thiols, other redox agents, and detergents also have complex effects on the activity of both iso-enzymes (2).Studies with the kinetic characterization of these isoenzymes led to the present understanding of the role of cyclic GMP in smooth muscle relaxation. Azide, added to inhibit GTPase ac-tivity in crude enzyme preparations, was found to activate the enzyme (15). While some hormones, autocoids, and otheragents were able to increase cyclic GMP accumulation in intact tissues, these agents had no effects on guanylate cyclaseactivity in broken